Method and apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate

ABSTRACT

Apparatus and a concomitant method for electrostatically depositing select doses of medicament powder at select locations on a substrate. Specifically, the apparatus contains a charged particle emitter for generating charged particles that charge a predefined region of a substrate and a charge accumulation control circuit for computing the amount of charge accumulated upon the substrate and deactivating the emitter when a selected quantity of charge has accumulated. Additionally, a triboelectric charging apparatus charges the medicament powder and forms a charged medicament cloud proximate the charged region of the substrate. The medicament particles within the medicament cloud electrostatically adhere to the charged region. The quantity of charge accumulated on the substrate at the predefined region and the charge-to-mass ratio of the medicament powder in the cloud control the amount (dose) of medicament deposited and retained by the substrate. Consequently, this apparatus accurately controls both medicament dosage and deposition location. Furthermore, since the substrate can be of any dielectric material that retains an electrostatic charge, the apparatus can be used to deposit medicament on substrates that are presently used in oral medicament consumption, e.g., substrates that are used to fabricate suppositories, inhalants, tablets, capsules and the like.

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/471,889, filed on Jun. 6, 1995.

The invention relates to dry powder deposition techniques and moreparticularly, the invention relates to a technique for electrostaticallydepositing a dry powder medicament in accurate, repeatable doses upon adielectric substrate.

BACKGROUND OF THE DISCLOSURE

Powdered medication is typically administered orally to a person as atablet or capsule, or as an inhalant. The prior art discloses a numberof techniques for administering doses of inhalable dry powders to thelungs of a patient. Generally, inhalers are mechanical systems thatgenerate a metered cloud of medicament powder for inhalation by apatient. Many of these prior art inhaler devices use chlorofluorocarbon(CFC) gas to facilitate generating a metered cloud of medicament forinhalation. However, since CFCs are no longer used in consumer products,other techniques for generating the medicament cloud have been explored.

One example of a non-CFC, prior art inhaler is disclosed in U.S. Pat.No. 4,811,731 issued Mar. 14, 1989 (the "'731 patent"). This patentdiscloses an inhaler that contains a plurality of measured doses ofmedicament stored in a blisterpack. Upon use, one of the blisters in theblisterpack is punctured and a patient inhales the medicament from thepunctured blister via a mouthpiece of the inhaler. In the '731 patent,the medicament dosage is measured and deposited in each blister of theblisterpack using conventional, mechanical measuring and depositingtechniques. Detrimentally, such mechanical deposition techniques do notapply repeatable doses of medication into each blister of theblisterpack. Typically, some of the medicament adheres to the mechanicaldeposition system and, as such, reduces the amount of medicationdeposited into a given blister. The degree of adhesion depends upon theenvironment in which the deposition is conducted, e.g., the ambienthumidity, temperature and the like. Since a mechanical depositionprocess is used to apply medicament to other orally administrableplatforms, the same dose variation evident in inhaler doses occurs forother platforms as well. As such, a more accurate technique is needed inthe art for depositing medication into any orally administrable platformincluding inhalers, tablets, capsules, suppositories, and the like.

An example of a technique for producing orally administered medicationtablet or capsule form is disclosed in U.S. Pat. No. 4,197,289 issuedApr. 8, 1980. This technique utilizes an electrostatic depositionprocess for depositing a medicament upon an edible substrate that isreferred to in the '289 patent as a "web". Using a conventional coronacharging technique, this process continuously charges the web as the webmoves past the charging element. Thereafter, the web passes though acompartment containing a medicament cloud. The medicament in the cloudis attracted to the charged web and becomes deposited thereupon, i.e.,the web becomes "loaded". A spectroscopic monitoring system determinesthe amount of medication that has been deposited on the web andgenerates a control signal that regulates the amount of medicamentwithin the cloud chamber. As such, the '289 deposition technique uses anactive feedback system to regulate the deposition process. To completethe process, the loaded web is cut into individual units that can becombined with one another to define a medicament dose, e.g., aparticular number of individual web units defines a single dose of themedication. The combined units are then encapsulated to form individual,orally administrable doses of medication.

A disadvantage of the '289 technique is the requirement for an activefeedback system to control the deposition process. Such systems aretypically complex and require an integrated medicament measuring systemto generate the control signals, e.g., such as the spectroscopicmonitoring system of the '289 patent. In using a feedback system, the'289 technique attempts to uniformly deposit the medicament across theentire web. Dosage control is therefore accomplished not by changing thedeposition quantity upon the web, but rather by combining a number ofweb units to form a dose. As such, the dosage control process is undulycomplicated. For example, to generate a uniform deposit of medicament,the electrostatic charge on the web must be uniform, the rate at whichthe web passes the charging element and the cloud compartment must beconstant, and the feedback system must accurately measure the amount ofdrug on the web and accurately control the amount of medication in thecloud compartment. Thereafter, assuming the medication was uniformlydeposited on the web, the web must be accurately cut into units that canbe combined and encapsulated to form doses of the medication. Each ofthe encapsulated doses is supposed to contain the same amount ofmedication as all other doses. However, such a complicated process isprone to error.

Therefore, a need exists in the art for a medicament deposition processthat electrostatically deposits specific quantities of dry powdermedication at particular locations on a dielectric substrate.Additionally, a need exists in the art for a technique for quantifyingan amount of electrostatic charge accumulated on the substrate and touse the quantified charge value to regulate the quantity of medicamentdeposited on the substrate.

SUMMARY OF THE INVENTION

The disadvantages heretofore associated with the prior art are overcomeby an inventive technique for electrostatically depositing dry powderedmedication at specific locations upon a dielectric substrate.Specifically, a conventional ionographic print head is utilized tocharge a particular region of a substrate. The substrate is a planar,dielectric layer positioned upon a conductive plate. To form adielectric layer that is in contact with the conductive plate, thedielectric layer may be deposited upon the plate, the dielectric layermay be in contact with but independent from the plate, or the plate maybe metallic plating deposited upon a lower surface of the dielectriclayer.

In operation, a potential is applied between the plate and the printhead such that the plate attracts ions generated by the print head.Consequently, the ions electrostatically charge a region of thedielectric layer that lies between the plate and the print head.Selectively positioning the print head relative to the substrate selectsparticular regions of the substrate upon which to "print" the charge.The amount of charge accumulated at any one location depends upon thedwell time of the print head over that particular location and the ioncurrent between the print head and the plate.

Once a charge is accumulated on the substrate, a triboelectric chargingprocess produces a charged cloud of medicament proximate the chargedregion of the substrate. The triboelectric charging process mixes, in aglass container, the dry powder medicament with a plurality of glass orplastic beads. The mixing action charges the medicament. A gas is thenused to blow the charged medicament from the container and into a cloudproximate the charged surface of the substrate. The medicament particlesare typically oppositely charged with respect to the charge on thesubstrate. As such, the medicament deposits itself upon the chargedregion of the substrate. The deposition pattern of the medicamentmatches a charge pattern "printed" by the print head and the amount ofmedicament that adheres to the patterned region is proportional to theamount of charge accumulated by the substrate. Consequently, using theinvention, the medicament can be accurately positioned on a substrateand the dose can be accurately controlled by controlling the amount ofcharge accumulated on the substrate.

In one embodiment of the invention, the print head is combined withcharge measuring apparatus for quantifying the charge accumulated on thesubstrate. The measuring apparatus measures the DC current (ion current)between the print head and the conductive plate. Specifically, the plateis connected to an integrator that charges a capacitor as the ionsbombard the substrate. A comparator compares the integrator outputsignal to a threshold level. The threshold level represents a specificamount of charge to be accumulated on the substrate. When the integratoroutput signal exceeds the threshold level, the comparator deactivates anAC signal source that generates the ions within the print head. As such,the print head stops generating ions and charge no longer accumulates onthe substrate. Consequently, a specific amount of charge has beenapplied to the substrate and, when the medicament cloud is applied tothe charged surface, a particular amount of medicament adheres to thesubstrate. In this manner, the charge control process very accuratelycontrols the quantity of medicament that is retained by the substrate.

In a further embodiment of the invention, a reverse development processis used to electrostatically deposit medicament powder on a substrate.In a reverse development process, a charge is deposited over the entiresubstrate surface, except in regions where the medicament is to bedeposited. To pattern the charge and generate uncharged regions, eitherthe print head is selectively modulated (activated and deactivated) asit is moved over the surface of the substrate or a photoconductivesubstrate is used such that, after charging, light is used toselectively remove charge from particular regions of the substrate. Ineither instance, if, for example, a negative charge is applied to thesubstrate, a negative charge is also applied to the medicament. As such,the medicament adheres to the substrate in the uncharged regions only,i.e., an electrostatic force is produced between the conductive plateand the medicament in the uncharged regions.

The types of substrates upon which the medicament can be deposited varywidely depending upon the ultimate application of the medication. Forexample, in an inhaler application, the substrate can be a flat, ceramicdisk upon which a plurality of medicament doses are positioned. A usermay selectively remove and inhale each dose of the medicament from thedisk using a venturi effect inhaler device. Alternatively, the disk maybe a fabricated of a woven or perforated dielectric material. In thiscase, a user can directly position a delivery tube within the inhalerdevice over a selected dose of medicament stored on the disk. The userthen inhales air through the delivery tube and the air flow releases themedicament from the dielectric. The released medicament continuesthrough the delivery tube into the user's lungs.

In a further example of the invention being used to producepharmaceutical substrates, including capsules, tablets, vaginal andrectal suppositories and the like, the electrostatic depositiontechnique of the invention is used to electrostatically deposit specificquantities of powdered medicament upon an edible or otherwisebiodegradable substrate. The substrate is then encapsulated in an inertmaterial to form a capsule, tablet, or suppository. Substrates usefulfor this application are typically polymeric substances that preferablyself-destruct or degrade in body fluids and/or enzymes. However, thesubstrate can be an indestructible substance that is readily eliminatedfrom the body once the medicament has been released from the substrateinto the body. Additionally, for example, the deposition technique ofthe invention can be used to deposit directly onto a pharmaceuticalsubstrate including an inhaler substrate, a capsule, tablet orsuppository. Thus, the present invention further provides a method ofmanufacturing a pharmaceutical substrate with medicament powderdeposited thereon, comprising electrostatically depositing themedicament powder on the substrate. Preferably, the electrostaticdeposition of the medicament occurs on a predefined region of thepharmaceutical substrate, such as the surface of a tablet inside theedges so that the edges of the tablet may be sealed.

BRIEF DESCRIPTION OF THE DRAWINGS

The teachings of the present invention can be readily understood byconsidering the following detailed description in conjunction with theaccompanying drawings, in which:

FIG. 1 depicts a cross-sectional view of an ionographic print head and adielectric substrate supported by a conductive plate;

FIG. 2 depicts a schematic drawing of a charge accumulation controlcircuit for use in conjunction with the print head of FIG. 1;

FIG. 3 depicts a cross-sectional view of a triboelectric chargingcontainer for charging a medicament powder and a cross-sectional view ofa portion of a substrate upon which the charged medicament powder isdeposited;

FIG. 4 depicts a flow chart of the electrostatic deposition process;

FIG. 5 depicts a top, perspective view of a substrate that has beencharged using a reverse development charging technique;

FIG. 6 depicts a cross-sectional view of the substrate along line 6--6in FIG. 5; and

FIG. 7 depicts a perspective view of an illustrative substrate havinghad dry powder deposited at a plurality of select locations thereuponand an illustrative inhalation device for releasing the medicament fromthe substrate.

FIG. 8 is a graphical representation of the charge density ofelectrostatically printed dots in nanoCoulombs on the x-axis versus theleft-hand y-axis which shows the diameter of the dots in mils, with thedata points shown as open squares; and the right-hand y-axis which showsthe weight of the dots in micrograms, with the data points shown asclosed squares.

FIGS. 9A-C are optical micrographs of depositions of a medicament upon a2 cm² polypropylene substrate using ion printing. FIG. 9A shows dotshaving a diameter of about 75 mil; FIG. 9B shows dots having a diameterof about 45 mils, and FIG. 9C shows dots having a diameter of about 37mils.

To facilitate understanding, identical reference numerals have beenused, where possible, to designate identical elements that are common tothe figures.

DETAILED DESCRIPTION

The present invention is apparatus and a concomitant method forelectrostatically depositing a specific quantity of dry powdermedicament at select locations on a substrate. The apparatus contains anionographic print head, an AC signal supply for generating ions withinthe print head, a DC signal source for propelling the ions toward asubstrate, and a charge accumulation control circuit for computing theamount of charge accumulated upon the substrate and deactivating the ACsignal source when a specific quantity of charge has accumulated.Additionally, a triboelectric charging apparatus is used to charge themedicament powder and form a charged medicament cloud proximate apredefined region of the substrate that is charged by the print head.The medicament particles within the medicament cloud electrostaticallyadhere to the predefined region. The quantity of charge accumulated onthe substrate at the predefined region and the charge-to-mass ratio ofthe medicament powder in the cloud controls the amount (dose) ofmedicament that is deposited upon and retained by the substrate.Consequently, this apparatus accurately controls both medicament dosageand deposition location. Furthermore, since the substrate can befabricated of any dielectric material that will retain an electrostaticcharge, the apparatus can be used to deposit medicament on manysubstrates that are presently used in medicament consumption, e.g.,substrate materials used to fabricate suppositories, inhalants, tablets,capsules and the like.

Thus, according to the present invention, specific quantities ofpowdered medicament can be deposited onto a substrate. The substrate canthen be encapsulated, for example, to form a tablet. In addition toencapsulation, a pharmaceutical substrate having an electrostaticallydeposited powder thereon can also be formed by electrostatic depositiononto the pharmaceutical substrate itself provided that thepharmaceutical substrate can retain a corona charge for deposition ofthe medicament. In certain preferred embodiments, the pharmaceuticalsubstrate is an inhaler substrate, a tablet, capsule or suppository. Atablet, for example, can be tested to determine whether it can retain acorona charge as follows. The conductivity of a tablet can be determinedby measuring the DC impedance, by placing the tablet in an electricalcircuit between a voltage source and a picoammeter. The capacitance ofthe tablet can be measured by placing the tablet sample in parallel witha Hewlett Packard 4192A Low Frequency Impedance Analyzer set for 1 kHz.The tablets are preferably painted on both sides with a thin layer ofconductive silver paint to ensure good electrical contact.

If the tablet, as formulated, cannot retain a corona charge, the tabletis preferably coated, for example, with a surface coating that retains acorona charge on the surface of the tablet. For example, an ediblepolymer can be used for the surface coating, such as natural orchemically modified starches and dextrins including lactose; otherpolysaccharides such as pectin, acacia, xanthin gum, guar gum and algin;phospholipids such as lecithin; proteins such as gelatin; cellulosederivatives such as sodium carboxymethylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose; syntheticpolymers such as polyvinylpyrrolidone and polyvinyl alcohol; or otheredible polymers, and preferably those which are hydrophobic. See alsoU.S. Pat. No. 4,197,289, which is incorporated by reference herein inits entirety.

Once the medicament is deposited on the tablet, the medicament ispreferably sealed onto the tablet by coating the tablet. In certainembodiments, the tablet has an indentation for deposition of medicament,the indentation preferably being filled when the desired amount ofmedicament is deposited. The tablet is preferably sealed afterdeposition.

Thus, the present invention further provides a method of manufacturing apharmaceutical substrate with medicament powder deposited thereon,comprising electrostatically depositing the medicament powder on thesubstrate. In certain preferred embodiments, the pharmaceuticalsubstrate is, for example, an inhaler substrate, a tablet, capsule orsuppository. Preferably, the electrostatic deposition of the medicamentoccurs on a predefined region of the substrate, such as the surface of atablet inside the edges so that the edges of the tablet may be sealed.

FIG. 1 depicts apparatus for depositing a predefined quantity of chargeat a particular location on a dielectric substrate 110. Specifically,the apparatus 100 is comprised of an ion emitter commonly referred to asan ionographic print head 102, AC and DC signal sources 104 and 106 forthe print head, a charge control circuit 108 and a dielectric layer 110(substrate) supported by a conductive plate 112. More specifically, theprint head 102 contains a first electrode 114 separated from a secondelectrode 116 by an insulator 118. The AC signal source 104 typicallysupplies a 5 MHz RF signal of approximately 1500 peak-to-peak voltsacross the first and second electrodes. The second electrode contains anaperture that forms an ion generation region 120. The AC signal causesan electric field between the electrodes to form a plasma in region 120.Specifically, the air within this region becomes ionized forming theplasma. To remove the ions 121 from the region and propel them towardsthe substrate, a screen grid 122 is positioned in a spaced-apartparallel relation to the second electrode 116 and the grid 122 containsan aperture 126 that is coaxially aligned with the region 120.Insulating layer 124, located between the screen grid 122 and the secondelectrode 116, maintains the screen grid 122 in this spaced-apartrelation with respect to the second electrode 116.

Typically, to control ion extraction from region 120, a DC voltagesource 128 is connected between the screen grid and the secondelectrode. However, empirical study indicates that a voltage of zerovolts applied between the second electrode and the screen grid permitseffective extraction of ions from region 120. As such, the secondelectrode can be electrically connected to the screen grid as indicatedby dashed line 130. However, the optimum screen grid to second electrodevoltage may vary depending upon the screen grid bias voltage, the ACvoltage and frequency, and the particular structure of the ion emitter.Thus, for best results, a variable DC voltage source 128 should be usedto optimize ion extraction.

A bias voltage from a DC signal source 106 is applied to the conductiveplate 112 and the screen grid 122. The source 106 supplies a biasvoltage of approximately 1200 volts that propels the ions through thescreen grid aperture 126 toward the substrate 110. Additionally,acceptable charge deposition has resulted from bias voltages in therange of 400 to 600 volts. The ions form a path that generally followsthe electric field lines of force spanning between the screen grid andthe plate. The gap between the grid and the substrate is approximately20 mils. Also, the screen grid, by having this bias voltage appliedthereto, selects the polarity of ion that is propelled to the substrate,e.g., a negative biased screen grid propels positive ions toward thesubstrate, while a positive bias propels negative ions toward thesubstrate. Typically, the screen grid is negatively biased and theconductive plate is maintained at a ground (0 volt) potential. In thismanner, the screen grid assists in the propulsion of the negative ionsto negatively charge the substrate at a location on the substrate thatis directly below the print head.

The ion current that flows from the screen grid 122 to the plate 112,during any given unit of time, and returns through DC source 106 isequal to the amount of charge accumulated on the substrate. As such, tomeasure the charge accumulation and control the amount of chargeaccumulated on the substrate, a charge control circuit 108 is connectedin series with the DC signal source. The charge control circuit (whichis discussed in detail below with respect to FIG. 2) measures thecurrent flowing between the plate 112 and the screen grid 122. When thecurrent attains a predefined level, the charge control circuitdeactivates the AC signal source and, consequently, halts the flow ofions to the substrate. In essence, the charge control circuit modulatesthe AC signal from the AC signal source. Upon cessation of the ion flow,no further charge accumulation occurs on the surface of the substrate.Thus, the substrate attains and maintains a predefined charge quantityat a particular location on the substrate.

In the foregoing discussion, the print head was discussed as being anion emitter having two electrodes and a screen grid. Such emitters arecommercially available as model 1013527 manufactured by Delphax, Inc.located in Toronto, Canada. It should be understood that this particularemitter arrangement is meant to be illustrative and that other electrodeand grid arrangements are available in the art that would produce thenecessary localized charge accumulation on the surface of the substrate.Furthermore, the emitter can also be an electron beam emitter thatpropels a stream of electrons toward the substrate to locally charge thesurface of the substrate. As such, the invention described hereinencompasses all possible forms of charged particle emitter that canconceivably charge the surface of a dielectric substrate in a localizedmanner.

Although an "off-the-shelf" ion emitter will sufficiently charge thesubstrate, empirical study indicates that superior charge deposition isachieved when using a smaller screen grid aperture 126 than is generallyavailable in an off-the-shelf emitter. As such, to reduce the size ofthe charge accumulation area when using the model 1013527 Delphaxemitter, the standard emitter is fitted with a conductive plate (aretrofit screen grid) that reduces the typical 6 mil diameter screengrid aperture to a 1-2 mil diameter aperture. In other words, theretrofit screen grid having a 1-2 mil diameter aperture is coaxiallyaligned with the standard screen grid aperture to form a compositescreen grid with a 1-2 mil diameter aperture. The screen grid biasvoltage is applied to the retrofit screen grid. Of course, rather thanusing a retrofit screen grid, the emitter could merely be fabricatedwith a 1-2 mil screen grid aperture.

FIG. 2 depicts a schematic diagram of the charge control circuit 108.The circuit contains a low pass filter (LPF) 200, an integrator 202, acomparator 204 and a threshold level source 212. The integrator furthercontains a capacitor 206, a capacitor discharge component such as amechanical, electromechanical, or solid state switch 208, and a highimpedance amplifier 210. Specifically, an input port of the filter 200is connected to the conductive plate 112 that supports the dielectricsubstrate 110. The filter removes any RF energy (e.g., AC signal fromthe AC signal source) that is coupled from the emitter 102 to the plate112, leaving only the DC signal that represents the ion current. Theoutput port of the filter is coupled to the capacitor 206. The capacitoris connected between the output port and ground. As such, the capacitorcharges to a voltage that represents the magnitude of the DC signalproduced by the filter 200. The capacitor discharge component 208 isconnected across the capacitor for intermittently discharging the signalaccumulated in the capacitor. The discharge is typically accomplishedbetween depositions of medicament to remove the residual charge from aprevious deposit. The high impedance amplifier 210 is connected to thecapacitor and output port of the filter such that the signal accumulatedon the capacitor is amplified to a useful level.

The output of the integrator 202, the integrated signal, is applied toone port of the comparator 204. The magnitude of the integrated signalis directly proportional to the amount of charge accumulated upon thedielectric substrate 110, e.g., as the charge accumulates more ioncurrent flows and the magnitude of the integrated signal increases. Asecond port of the comparator is connected to a threshold voltage source212. The source 212 provides a threshold signal to which the comparatorcompares the integrated signal. When the integrated signal exceeds thethreshold level, the charge control circuit 108 deactivates the ACsignal source driving the print head. Conversely, as long as theintegrated signal magnitude is less than the threshold level, the ACsignal source remains activated and the charge accumulates upon thesubstrate.

The charge accumulation on the substrate is proportional to the size ofthe region that is charged by the print head. In accordance withionographic printing terminology, this region, which is typicallycircular, is commonly referred to as a "dot size". The dot size isrelated to the accumulated charge by the following equation:

    dot size=(dot size.sub.0) ##EQU1## where: dot size is a diameter of a circular region in which charge is accumulated on the substrate;

q is the accumulated charge quantity to produce a particular dot size;and

q₀ is a reference charge quantity to generate reference dot size (dotsize₀).

The reference charge quantity and dot size are empirically predeterminedfor a particular dielectric material and dielectric material thickness.Once the reference charge quantity and reference dot size aredetermined, equation (1) is used to compute the dot size for any givencharge quantity. Thus, the threshold level in the charge control circuitis correlated to one or more dot sizes. As such, the threshold level isset to deactivate the AC signal source when a particular level isexceeded such that a particular dot size is generated for that thresholdlevel. Further, a series of selectable threshold levels can be providedsuch that a user can select a particular dot size to be generated for aparticular medicament being deposited at that time. Thus, this form ofmedicament deposition is very flexible and very useful in controllingthe medicament dose that is deposited upon the substrate.

Once the substrate is charged, the medicament must then be depositedupon the charged region of the substrate. In this regard, a medicamentcloud is provided proximate the charged region of the substrate. Themedicament particles in the cloud, being positively charged (if thesubstrate is negatively charged), are attracted to the negativelycharged region of the substrate and electrostatically deposit themselveson the charged region of the substrate. Of course, the medicament cloudis negatively charged if the substrate has been positively charged.

FIG. 3 depicts a cross-sectional view of apparatus 300 for charging themedicament particles and depositing the charged particles upon thesubstrate. Specifically, the invention uses a triboelectric chargingtechnique to charge the medicament. Such a technique effectively chargesthe medicament particles such that, when dispersed into a cloud, thecharge-to-mass ratio on each particle is substantially uniformthroughout the cloud. Consequently, given a repeatable quantity ofcharge on the substrate and such a repeatable charge-to-mass ratio onthe medicament particles, a repeatable amount of medicament is attractedto and remains electrostatically adhered to the substrate. Theelectrostatic attraction or adhesion between the medicament powder andthe substrate remains, without significant degradation, for months.

Medicament charging and deposition apparatus 300 contains atriboelectric charger 302, medicament powder 304, and the chargedsubstrate 110 supported upon a conductive plate 112. The substrate has acharged region 310 (dot size) that has been locally charged aspreviously discussed with an ion or electron emitter. The triboelectriccharger 302 is a cylindrical, glass container 306 containing a pluralityof glass or plastic beads 308 (e.g., four beads) and the powderedmedicament 304. Illustratively, the beads have a diameter of between 50and 200 microns and are fabricated of one of the following materialsTeflon, kynar, polypropylene, maroon polypropylene, fluoro-treatedglass, glass, amino-treated glass, polystyrene, white miliken and thelike. The container 306 has a mesh, typically wire, at each end. Themesh defines openings (e.g., 400 mesh screen) that permit the medicamentpowder to ingress and egress from the container. In use, the medicamentis added to the container, the mesh ends of the container are closed offand the beads and medicament mixture is shaken for 1 to 10 minutes.During the shaking process, a charge accumulates on the particles of thepowder. Once charged, a gas (e.g., air or nitrogen) is blown through thecontainer and medicament particles form a cloud proximate the surface ofthe substrate.

The amount and polarity of the charge on the medicament particlesdepends upon the fabrication material of the beads. By measuring thecharge-to-mass ratio of the powder using a faraday cage, the inventorshave found that by selecting a particular bead material the chargecharacteristics are controllable. For example, charging a mometasonefuroate (MF) powder in a glass container using four beads having 50 to100 micron diameters at 70 degrees Fahrenheit and 45% relative humidity,resulted in the charge-to-mass ratios for various bead materials shownin Table 1.

                  TABLE 1                                                         ______________________________________                                        Bead Material  Charge Polarity                                                                          Ratio (μC/gm)                                    ______________________________________                                        Teflon         positive   35                                                    Kynar positive 30                                                             Polypropylene positive 6.5                                                    Maroon polypropylene positive 10                                              Fluoro-treated glass positive 17.8                                            Glass negative 6.5                                                            Amino-treated glass negative 39.8                                             Polystyrene negative 42.7                                                     White miliken negative 7.7                                                  ______________________________________                                    

By appropriate selection of the bead material, the charge-to-mass ratiocan be varied form 6.5 to 43 μC/gm and the charge is either positive ornegative. When accurately depositing a medicament, a low microgramquantity of medicament (e.g., 20-40 μg) requires a relatively highcharge-to-mass ratio and a high microgram quantity of medicament (e.g.,20-40 μg) requires a relatively low charge-to-mass ratio. Using thetriboelectric medicament charging technique in combination with theelectrostatic substrate charging technique, a 10 to 200 μg quantity ofmedicament can be accurately positioned on the substrate. Furthermore,the adherence of such quantities of medicament to a 2 mil thick,polypropylene substrate is strong enough to withstand a 48 inch droptest without dislodging any of the medicament from the substrate. Thissubstantial adhesion property is attributed to electrostatic and shortrange van der Waals forces.

Once deposited, the substrate is positioned near a vacuum system toremove any medicament powder that has not electrostatically adhered tothe substrate. In a practical medicament dosing substrate, a pluralityof locations on the substrate are charged and then medicament isdeposited at each of the charged locations. Thereafter, the vacuumsystem removes any excess medicament powder that is not adhered to thecharged locations.

Alternatively, since the unadhered medicament powder (background powder)is typically a relatively small quantity of medicament, it can simply beleft on the substrate. If this approach is used, the amount of chargedeposited should be slightly reduced such that slightly less medicamentis adhered to the substrate.

FIG. 4 depicts a flow chart summarizing the process used toelectrostatically deposit medicament onto a substrate. Depositionprocess 400 begins, at step 402, by positioning the print head over aparticular location on a substrate. At step 404, a user selects the dotsize to be "printed" by selecting a threshold level for the chargecontrol circuit. The process, at step 406, activates the print head andbegins bombarding the selected location on the substrate with ions. Theprocess queries, at step 408, whether the threshold level has beenexceeded by the accumulated charge on the substrate. If the query isnegatively answered, the print head remains active and charge continuesto accumulate on the substrate. When the query of step 408 isaffirmatively answered, the process, at step 410, deactivates the printhead. At this point in the process a "dot" of charge having a diametercommensurate with the dot size selected in step 404 has been depositedat the selected location upon the substrate. Of course, rather than asingle dot, the print head could be moved relative to the substrate toform a charged pattern on the substrate, e.g., a line, a square, acircle, and the like.

Once the charge is deposited, the triboelectric charging apparatusproduces a charged cloud of medicament proximate the surface of thesubstrate. Specifically, the process, at step 412, produces this cloudof medicament as described above with respect to FIG. 3. A predefineddose of medicament adheres to the charged dot on the substrate. Asdiscussed above, the quantity of medicament in the dose depends on thecharge accumulated on the substrate and the charge-to-mass ratio ofcharge on the medicament powder. At step 414, excess medicament isremoved, for example, by a vacuum system. The excess medicament can berecycled for deposition at another time. Lastly, at step 416, thesubstrate and its medicament are packaged.

The foregoing electrostatic deposition process can further be used inwhat is known as a reverse development process. In general, the reversedevelopment process scans the print head over the substrate (or thesubstrate can be moved past the print head) to deposit charge at alllocations on the substrate except those locations where the medicamentis to be deposited.

FIG. 5 depicts a top view of a disk-shaped substrate 500 having aplurality of medicament deposition locations 502. The gray area on thesubstrate indicates the area in which a charge is deposited by the printhead. Conversely, locations 502 contain no charge.

As depicted in the cross-sectional view of a portion of the substrate502 in FIG. 6 taken along line 6--6 in FIG. 5, if the substrate chargeis negative, the conductive plate 112, positioned beneath the substrate500, is positively charged across its entire surface that contacts thesubstrate 500. The medicament 504 is negatively charged using, forexample, the triboelectric charging technique discussed above. Thenegatively charged medicament electrostatically adheres to the substrate500 in uncharged region 502, i.e., the negatively charged medicament isattracted to the positively charged plate. Additionally, the negativelycharged medicament is repelled from the negatively charged surface ofthe substrate. Consequently, medicament only accumulates and adheres tothe uncharged substrate regions 502. To release the medicament, theplate is discharged, typically by grounding. Such discharge removes theelectrostatic force maintaining the medicament upon the substrate.Consequently, once the charge is removed, the medicament can be easilyremoved from the substrate using a venturi or direct inhalation device(as discussed below with respect to FIG. 7). To facilitate release ofsingle medicament doses, the conductive plate is segmented (orpatterned) and each plate segment is located below each region 502. Assuch, each plate segment can be individually charged and discharged.Thus, each dose of medicament can be individually released from thesubstrate.

A variation of the reverse deposition technique forms another embodimentof the invention. This alternative involves utilization of aphotoconductive disk as a substrate upon which the medicament isdeposited. Illustratively, the photoconductive disk is a polymericsubstrate coated with a photoconductive zinc oxide in a resin binder. Aprint head charging technique is used to negatively charge the entiresurface of the disk. Thereafter, a light mask having a plurality ofapertures therethrough is positioned over the substrate and the mask isbathed in light. Consequently, the substrate surface exposed to thelight via the apertures in the mask is discharged of the negativecharge. After the mask is removed, the disk is charged in a manner thatresembles the substrate depicted in FIG. 5, i.e., charge is deposited inall locations except locations where the medicament is to be deposited.The negatively charged medicament powder is deposited in the unchargedregions in the same manner as described above with respect to FIG. 6.The medicament powder is released from the substrate by exposing aselected dose of the medicament and an area surrounding the selecteddose to light. Such light exposure discharges the electrostatic forceand releases the medicament powder from the substrate. Thereafter, themedicament can be inhaled using a venturi or direct inhalation device asdiscussed below.

FIG. 7 depicts an illustrative substrate having medicament deposited atpredefined locations using one of the electrostatic deposition processesdiscussed above with respect to FIGS. 4, 5 and 6. The substrate 110 ofFIG. 7 is a disk shaped dielectric that contains a plurality oflocations 310 to which medicament 304 electrostatically adheres. Acentral hole 700 is provided to permit the substrate to be supportedwithin an inhaler device 702. This exemplary inhaler device 702 uses theventuri principle to extract the medicament from the substrate. Theinhaler contains a housing (not shown) that surrounds the substrate andsupports the venturi inhaler apparatus 704 and the substrate 110. Theventuri inhaler apparatus contains a main air flow tube 710 having amouthpiece 706 and an inlet end 708. Approximately mid-way along themain air flow tube is a medicament tube 712 that orthogonally intersectsand is coupled to the main tube 710. The medicament tube 712 ispositioned over a medicament location 310 by rotating the substrate 110relative to the venturi apparatus 704. A patient then inhales throughthe mouthpiece 706 drawing air through inlet end 708 of the tube 710. Asair flows toward the mouthpiece 706, the venturi effect also draws airthrough tube 712. As air is drawn through tube 712, the medicament isdislodged from the substrate and carried to the patient's mouth. Whenanother dose is required, the patient rotates the substrate to the nextdose on the disk and again inhales the medicament.

To permit a substantial air flow along tube 712, the substrate, ratherthan being a solid layer of dielectric material, may be a woven orperforated substrate. Such substrates include a metallic mesh coatedwith a dielectric material such as Teflon, a textile such as silk, aperforated solid dielectric layer, and the like. The perforations aresmall relative to the particle size of the medicament, but large enoughto allow air to pass therethrough. As such, when a patient inhales onthe mouthpiece, air passes through the substrate 110 and along tube 712.The air flow carries the medicament to the patient.

Additionally, when using a perforated substrate, a venturi effectinhaler is not necessary and can be substituted with a simple inhalationtube. Such an inhaler device contains a flexible inhalation tubesupported by a housing and having an inlet end located proximate amedicament location. In essence, this is the venturi inhalationapparatus without a main air flow tube 710, where the patient merelyinhales on the medicament tube 712. In use, an inlet end of aninhalation tube is positioned proximate a medicament location byrotating the substrate within the housing. Thereafter, the patientsimply inhales the medicament directly from the perforated substrate,through the inhalation tube and into their lungs. The perforatedsubstrate significantly increases the velocity of the air flow thatremoves the medicament from the substrate over that of a venturi effectdevice used in combination with a solid substrate.

Those skilled in the art will realize that many other forms of inhalerdevices can be employed to dislodge the medicament from the substrate,including those that employ compressed gas or air to remove themedicament and generate a inhalable cloud. Any of these inhaler devicesare to be considered within the scope of the invention.

In each of the foregoing embodiments of the invention, the substrate maybe fabricated of Teflon, polystyrene, polypropylene and the like. Ingeneral, any material that will retain an electrostatic charge issufficient. The substrate, may or may not be perforated to enableinhalation of air through the substrate as discussed above. In a furtherexample of the invention being used to produce oral medication,including capsules, tablets, vaginal and rectal suppositories and thelike, the electrostatic deposition technique of the invention is used toelectrostatically deposit specific quantities of powdered medicamentupon an edible substrate such as cellulose. The substrate is thenencapsulated in a inert material to form a capsule, tablet, orsuppository. Substrates useful for this application are typicallypolymeric substances that preferably self-destruct or are degraded inbody fluids and/or enzymes. However, the substrate can be anon-destructible substance that is readily eliminated from the body oncethe medicament has been released into the body from the substrate.

Although various embodiments which incorporate the teachings of thepresent invention have been shown and described in detail herein, thoseskilled in the art can readily devise many other varied embodiments thatstill incorporate these teachings.

The accuracy of deposition using methods and apparatus of the inventionis further illustrated by the following non-limiting example.

EXAMPLE 1 Accuracy of Deposition of Medicament onto Inhaler Substrate

The correlation between the amount of charge generated in the substrateand the amount of medicament deposited was determined by measuring thecurrent applied, the time in which the current was applied, the totalcharge deposited, and the average maximum weight for a charge:mass ratioof 10 μC/g. The results are shown in Table 2 below.

                  TABLE 2                                                         ______________________________________                                                                           ave. max.                                      Total Dot weight for                                                        Current Time charge Diameter q/m = 10                                         (nA) (seconds) (nC) (mils) μC/g                                          ______________________________________                                        3.5      0.13     0.45      37     6.5                                          12 0.13 1.56 45 22                                                            16.5 0.13 2.15 54 30                                                          19.5 0.13 2.54 60 37                                                          40 0.13 5.7 75 73                                                             40 0.13 17.1 99 140                                                         ______________________________________                                    

The data in the foregoing table is depicted graphically in FIG. 8, whichprovides a y-axis on the left side of the graph showing the diameter ofthe dots in mils, with the data points shown as open squares; a y-axison the right side of the graph showing the weight of the dots inmicrograms, with the data points shown as closed squares; and an x-axisshowing the charge density of the dots in nanoCoulombs. The data, asdepicted in the graph in FIG. 8, shows that the relationship between thecharge density of the dot and the diameter of the dot is substantiallylinear, and the relationship between the charge density of the dot andthe weight of the dot are also substantially linear. Thus, the chargedensity can be used to accurately determine a precise amount ofmedicament to be deposited upon the inhaler substrate using the ionprinting method. Using this methods, small dosages from 10 μg to 100 μgof medicament were accurately deposited, within ±10%.

FIGS. 9A-C are optical micrographs of depositions of a medicament upon a2 cm² polypropylene substrate using ion printing. FIG. 9A shows dotshaving a diameter of about 75 mil; FIG. 9B shows dots having a diameterof about 45 mils, and FIG. 9C shows dots having a diameter of about 37mils.

What is claimed is:
 1. Apparatus for electrostatically depositing apowder upon a selected region of a surface of a tablet, the apparatuscomprising:an ion emitter for generating ions; a tablet spaced apartfrom the emitter and located upon a conductive plate, where ions emittedfrom the ion emitter, upon impact with the selected region, locallycharge the tablet at the selected region; and a powder cloud generator,where the powder cloud generator generates a cloud of powder proximatethe selected region, where a plurality of powder particles within thecloud are electrostatically adhered to the selected region of thetablet.
 2. The apparatus of claim 1, wherein the apparatus is adaptedfor depositing a medicament powder.
 3. The apparatus of claim 1, furthercomprising:a charge accumulation controller, coupled to the emitter andthe conductive plate, for comparing the charge accumulated upon thetablet to a threshold charge value and for deactivating the emitter whenthe comparison generates a deactivation signal.
 4. The apparatus ofclaim 3, wherein the charge accumulation controller controls a size ofthe charged region on the tablet by measuring the accumulated charge onthe tablet relative to a reference charge value that corresponds to areference size of the charged region.
 5. The apparatus of claim 3,wherein the charge accumulation controller further comprises anintegrator for integrating the charge accumulated upon the tablet andfor generating a voltage value indicative of the accumulated charge onthe tablet.
 6. The apparatus of claim 5, wherein the charge accumulationcontroller further comprises a low pass filter connected between theconductive plate and the integrator.
 7. The apparatus of claim 1 whereinthe powder cloud generator is a triboelectric charging apparatus.
 8. Theapparatus of claim 7 wherein the triboelectric apparatus comprises aplurality of tribocharging beads that are fabricated of a selectedmaterial that generates substantially the same charge-to-mass ratio foreach particle of powder within the cloud of powder.
 9. The apparatus ofclaim 1 wherein the powder is deposited at two or more predefinedregions upon the tablet.
 10. Apparatus for electrostatically depositinga powder upon selected regions of a tablet, the apparatus comprising:acharged particle emitter for generating charged particles; a tabletspaced apart from the emitter and located upon a conductive plate, wherethe charged particles, upon impact with a predefined region of a surfaceof the tablet, locally charge the tablet at the predefined region; and apowder cloud generator, where the powder cloud generator generates acloud of powder proximate the predefined region on the tablet, where aplurality of powder particles within the cloud are electrostaticallyadhered to any region other than the predefined region of the tablet.11. The apparatus of claim 10 wherein the apparatus is adapted fordepositing a medicament powder.
 12. The apparatus of claim 10 furthercomprising: a charge accumulation controller, coupled to the emitter andthe conductive plate, for comparing the charge accumulated upon thetablet to a threshold charge value and for deactivating the emitter whenthe comparison generates a deactivation signal.
 13. The apparatus ofclaim 10 wherein the powder cloud generator is a triboelectric chargingapparatus.
 14. The apparatus of claim 13 wherein the triboelectricapparatus generates substantially the same charge-to mass ratio for eachparticle of medicament powder within the cloud of powder.
 15. Theapparatus of claim 10 wherein the medicament powder is deposited uponthe tablet at a plurality of regions other than the predefined region.16. Apparatus for electrostatically depositing a medicament powder uponselected region of a tablet, the apparatus comprising:a charged particleemitter for generating charged particles; a photoconductive tabletspaced apart from the emitter and located upon a conductive plate, wherethe charged particles, upon impact with a surface of the photoconductivetablet, charge the surface of the tablet; a light mask, applied to thecharged tablet surface, for selectively applying light to causedischarging of any region of the photoconductive tablet not covered bythe light mask; and a powder cloud generator where the powder cloudgenerator generates a cloud of medicament powder proximate thepredefined region on the tablet, where a plurality of powder particleswithin the cloud are electrostatically adhered to any region other thana charged region of the tablet.
 17. The apparatus of claim 16, whereapparatus is adapted for depositing a medicament powder.
 18. Theapparatus of claim 16 wherein the powder cloud generator is atriboelectric charging apparatus.
 19. The apparatus of claim 18 whereinthe triboelectric apparatus generates substantially the samecharge-to-mass ratio for each particle of medicament powder within thecloud of powder.
 20. The apparatus of claim 16 wherein the medicamentpowder is deposited upon the photoconductive tablet at two or moreuncharged regions.